From the Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas, Spain (A.S.-P., C.J., M.G., A.M.P.).
Functional Unit of Cerebrovascular Diseases, Hospital Clínic, Barcelona, Spain (F.M.-M., X.U., Á.C.).
Arterioscler Thromb Vasc Biol. 2018 Aug;38(8):1761-1771. doi: 10.1161/ATVBAHA.118.311284.
Objective- Hemorrhagic transformation is a serious complication of ischemic stroke after recanalization therapies. This study aims to identify mechanisms underlying hemorrhagic transformation after cerebral ischemia/reperfusion. Approach and Results- We used wild-type mice and Selplg and Fut7 mice defective in P-selectin binding and lymphopenic Rag2 mice. We induced 30-minute or 45-minute ischemia by intraluminal occlusion of the middle cerebral artery and assessed hemorrhagic transformation at 48 hours with a hemorrhage grading score, histological means, brain hemoglobin content, or magnetic resonance imaging. We depleted platelets and adoptively transferred T cells of the different genotypes to lymphopenic mice. Interactions of T cells with platelets in blood were studied by flow cytometry and image stream technology. We show that platelet depletion increased the bleeding risk only after large infarcts. Lymphopenia predisposed to hemorrhagic transformation after severe stroke, and adoptive transfer of T cells prevented hemorrhagic transformation in lymphopenic mice. CD4 memory T cells were the subset of T cells binding P-selectin and platelets through functional P-selectin glycoprotein ligand-1. Mice defective in P-selectin binding had a higher hemorrhagic score than wild-type mice. Adoptive transfer of T cells defective in P-selectin binding into lymphopenic mice did not prevent hemorrhagic transformation. Conclusions- The study identifies lymphopenia as a previously unrecognized risk factor for secondary hemorrhagic transformation in mice after severe ischemic stroke. T cells prevent hemorrhagic transformation by their capacity to bind platelets through P-selectin. The results highlight the role of T cells in bridging immunity and hemostasis in ischemic stroke.
出血转化是缺血性脑卒中再通治疗后的严重并发症。本研究旨在探讨脑缺血/再灌注后出血转化的机制。
我们使用野生型小鼠、不结合 P-选择素的 Selplg 和 Fut7 缺陷型小鼠以及淋巴细胞减少型 Rag2 小鼠。通过管腔内阻塞大脑中动脉，诱导 30 分钟或 45 分钟的缺血，并在 48 小时使用出血分级评分、组织学方法、脑血红蛋白含量或磁共振成像评估出血转化。我们耗竭血小板并将不同基因型的 T 细胞过继转移至淋巴细胞减少型小鼠。通过流式细胞术和图像流技术研究 T 细胞与血小板在血液中的相互作用。结果表明，只有在大梗死时，血小板耗竭才会增加出血风险。淋巴细胞减少易导致严重脑卒中后的出血转化，而过继转移 T 细胞可预防淋巴细胞减少型小鼠的出血转化。CD4 记忆 T 细胞是通过功能性 P-选择素糖蛋白配体-1 结合 P-选择素和血小板的 T 细胞亚群。不结合 P-选择素的小鼠比野生型小鼠的出血评分更高。将不结合 P-选择素的 T 细胞过继转移至淋巴细胞减少型小鼠不能预防出血转化。
本研究确定了淋巴细胞减少是小鼠严重缺血性脑卒中后继发性出血转化的一个以前未被认识的危险因素。T 细胞通过与血小板结合 P-选择素来预防出血转化。研究结果强调了 T 细胞在缺血性脑卒中的桥接免疫和止血中的作用。
